rs5936

Variant names:

• chr2-127423296-G-T
• rs5936
• NM_000312.4:c.423G>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000312.4(PROC):​c.423G>T​(p.Ser141Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.682 in 1,549,898 control chromosomes in the GnomAD database, including 362,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (36480 hom., cov: 36)
  • Exomes 𝑓: 0.68 (325588 hom.)
• Consequence: PROC NM_000312.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.81
• Publications: 38 publications found

Genes affected

PROC (HGNC:9451): (protein C, inactivator of coagulation factors Va and VIIIa) This gene encodes a vitamin K-dependent plasma glycoprotein. The encoded protein is cleaved to its activated form by the thrombin-thrombomodulin complex. This activated form contains a serine protease domain and functions in degradation of the activated forms of coagulation factors V and VIII. Mutations in this gene have been associated with thrombophilia due to protein C deficiency, neonatal purpura fulminans, and recurrent venous thrombosis.[provided by RefSeq, Dec 2009]

MIR4783 (HGNC:41874): (microRNA 4783) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.017).
• BP6: Variant 2-127423296-G-T is Benign according to our data. Variant chr2-127423296-G-T is described in ClinVar as Benign. ClinVar VariationId is 255809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.81 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.743 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000312.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROC	NM_000312.4	MANE Select	c.423G>T	p.Ser141Ser	synonymous	Exon 6 of 9	NP_000303.1	P04070-1
	PROC	NM_001375607.1		c.609G>T	p.Ser203Ser	synonymous	Exon 5 of 8	NP_001362536.1
	PROC	NM_001375602.1		c.606G>T	p.Ser202Ser	synonymous	Exon 6 of 9	NP_001362531.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROC	ENST00000234071.8	TSL:1 MANE Select	c.423G>T	p.Ser141Ser	synonymous	Exon 6 of 9	ENSP00000234071.4	P04070-1
	PROC	ENST00000883860.1		c.597G>T	p.Ser199Ser	synonymous	Exon 5 of 8	ENSP00000553919.1
	PROC	ENST00000883897.1		c.597G>T	p.Ser199Ser	synonymous	Exon 4 of 7	ENSP00000553956.1

Frequencies

GnomAD3 genomes AF: 0.692 AC: 105153 AN: 152022 Hom.: 36471 Cov.: 36

Gnomad AFR AF: 0.719

Gnomad AMI AF: 0.797

Gnomad AMR AF: 0.754

Gnomad ASJ AF: 0.692

Gnomad EAS AF: 0.572

Gnomad SAS AF: 0.521

Gnomad FIN AF: 0.685

Gnomad MID AF: 0.682

Gnomad NFE AF: 0.682

Gnomad OTH AF: 0.693

GnomAD2 exomes AF: 0.678 AC: 100470 AN: 148168 AF XY: 0.661

Gnomad AFR exome AF: 0.721

Gnomad AMR exome AF: 0.833

Gnomad ASJ exome AF: 0.711

Gnomad EAS exome AF: 0.562

Gnomad FIN exome AF: 0.677

Gnomad NFE exome AF: 0.686

Gnomad OTH exome AF: 0.686

GnomAD4 exome AF: 0.680 AC: 951060 AN: 1397762 Hom.: 325588 Cov.: 85 AF XY: 0.675 AC XY: 465408 AN XY: 689444

African (AFR) AF: 0.711 AC: 22409 AN: 31532

American (AMR) AF: 0.820 AC: 29353 AN: 35790

Ashkenazi Jewish (ASJ) AF: 0.709 AC: 17841 AN: 25146

East Asian (EAS) AF: 0.642 AC: 22955 AN: 35768

South Asian (SAS) AF: 0.522 AC: 41381 AN: 79228

European-Finnish (FIN) AF: 0.685 AC: 32803 AN: 47888

Middle Eastern (MID) AF: 0.656 AC: 3570 AN: 5444

European-Non Finnish (NFE) AF: 0.687 AC: 741677 AN: 1079010

Other (OTH) AF: 0.674 AC: 39071 AN: 57956

GnomAD4 genome AF: 0.691 AC: 105200 AN: 152136 Hom.: 36480 Cov.: 36 AF XY: 0.688 AC XY: 51165 AN XY: 74370

African (AFR) AF: 0.719 AC: 29847 AN: 41534

American (AMR) AF: 0.754 AC: 11548 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.692 AC: 2399 AN: 3466

East Asian (EAS) AF: 0.572 AC: 2948 AN: 5150

South Asian (SAS) AF: 0.520 AC: 2504 AN: 4820

European-Finnish (FIN) AF: 0.685 AC: 7256 AN: 10588

Middle Eastern (MID) AF: 0.685 AC: 200 AN: 292

European-Non Finnish (NFE) AF: 0.682 AC: 46321 AN: 67954

Other (OTH) AF: 0.686 AC: 1450 AN: 2114

Alfa AF: 0.697 Hom.: 19403

Bravo AF: 0.704

Asia WGS AF: 0.548 AC: 1905 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Thrombophilia due to protein C deficiency, autosomal dominant (3)
-	-	2	not provided (2)
-	-	1	Thrombophilia due to protein C deficiency, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	3.3
DANN	Benign	0.77
PhyloP100		-1.8
PromoterAI		0.0093	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs5936; hg19: chr2-128180872; COSMIC: COSV52164601; COSMIC: COSV52164601;